This invention relates to a tetrahydrobenzindole derivative or an intermediate thereof. Since this tetrahydrobenzindole derivative has the ability to bind to serotonin receptors in the living body, it also relates to the treatment and prevention of various diseases which are induced by the abnormality of serotonin controlling functions.
In the present society, the environment which surrounds us is sharply changing, and adaptation for it is becoming more and more difficult. Thus, a part which is too much for adaptation for the social environment is accumulated in our bodies as stress and sometimes causes abnormality of not only body functions but also mental functions. Under such circumstances, importance of drug therapy has been increasing more and more, so that development of effective drugs has been put forward.
Since the indication about the action of serotonin (5-HT) in the central nervous system, classification and distribution of serotonin receptors have been revealed gradually. By the detailed analysis of serotonin receptors using molecular biological means in recent years, 5-HT1 and its subtypes, 5-HT2 and its subtypes, 5-HT3, 5-HT4, 5-HT6, 5-HT7 and the like have been specified and a total of 14 different serotonin receptors have been proposed [R. D. Ward et al., Neuroscience, 64, 1105-1111 (1995)].
Studies on the physiological functions of serotonin receptors have also been making progress, and not only their relation to appetite, body temperature regulation, blood pressure regulation and the like body functions but also their relation to depression, anxiety, schizophrenia, sleep disorders and the like mental functions have been revealed [P. L. Bonate et al., Clinical Neuropharmacology, 14, 1-16 (1991)]. Actually, 5-HT1A receptor agonists, 5-HT2 receptor inhibitors and 5-HT re-uptake inhibitors are now used in the clinical field. It has been reported also that, since a drug group classified as atypical among already known schizophrenia treating drugs has the affinity particularly for serotonin receptor 5-HT6, the serotonin receptor 5-HT6 is closely related to the efficacy of these drugs [R. D. Ward et al., Neuroscience, 64, 1105-1111 (1995)].
It has been reported that several atypical schizophrenia treating drugs including clozapine have strong affinity for the 5HT6 receptor, and several typical schizophrenia treating drugs show high affinity for both of the 5HT6 and 5HT7 receptors [B. L. Roth et al., J. Pharmacol. Exp. Ther., 268 (3), 1403-1410, 1994]. Also, it has been reported that a 5HT1A partial agonist, buspirone, has high therapeutic effect for patients having both symptoms of depression and anxiety [Tollefson G. D. et al., Psychopharmacol. Bull., 27, 163-170, 1991]. In addition, the importance of serotonin receptors in various physiological functions was been reported in a large number, for example, it has been reported that certain N-butylpiperidines inhibit serotonin receptor 5-HT4 selectively and are useful for the treatment of irritable bowel syndrome [L. M. Gaster et al., J. Med. Chem., 38, 4760-4763, 1995], and it has been assumed that 5-HT7 exerts an important function in the human circadian rhythm regulation [T. W. Lovenberg et al., Neuron, 11, 449-458, 1993].
In addition, it is considered that they are exerting various physiological functions by distributing not only in human and animal brains but also broadly in smooth muscle tissues such as the spleen, stomach, ileum, small intestines, coronary vessel and the like [A. J. Sleight, DN and P, 214-223, 1997]. In consequence, creation of a substance which acts upon 5-HT7 receptor is considerably profitable for the studies of physiological functions in these organs and the treatment and prevention of diseases induced by functional abnormality in these organs.
The present inventors have already found a substance which has strong ability to bind to the 5-HT7 receptor in the living body. That is, according to the inventions by the present inventors (WO 98/00400, Japanese Patent Application No. 9-358380, Japanese Patent Application No. 9-358381, Japanese Patent Application No. 10-85913, Japanese Patent Application No. 10-136872, Japanese Patent Application No. 10-229709 and Japanese Patent Application No. 10-319336), there are provided novel tetrahydrobenzindole derivatives which strongly bind to 5-HT7 receptor in the living body and pharmaceutical compositions which comprise these compounds.
As described above, novel tetrahydrobenzindole derivatives which strongly bind to 5-HT7 receptor in the living body have been provided, but creation of a compound which selectively binds to the 5-HT7 receptor will be useful for the treatment and prevention of various diseases which are considered to be induced by the abnormality of central and peripheral serotonin controlling functions, such as mental diseases (manic-depressive psychosis, anxiety, schizophrenia, epilepsy, sleep disorders, biological rhythm disorders, migraine and the like), cardiovascular diseases (hypertension and the like) and gastrointestinal disorders, and will also provide medicaments having high safety that can prevent generation of unexpected side effects. It will also provide compounds which have high utility value in studies on the elucidation of physiological functions of 5-HT7 receptor whose functions are not clear yet.
Thus, the object of the invention is to provide a compound which has strong affinity for the 5-HT7 receptor in the living body and binds selectively to the 5-HT7 receptor.
In order to solve these problems, the present inventors have examined on various compounds. As a result, it was found that certain tetrahydrobenzindole derivatives have strong affinity for 5-HT7 receptor in the living body and selectively bind to 5-HT7 receptor, thereby resulting in the accomplishment of the invention. That is, according to the invention, novel tetrahydrobenzindole derivatives and pharmaceutical compositions which comprise these compounds are provided, and intermediates useful in producing these compounds are also provided. Accordingly, the invention comprises the following constructions.
1. A compound represented by formula (1): 
wherein R1 represents a hydrogen atom, a lower alkyl group or an aralkyl group; R2 represents a hydrogen atom, a halogen atom, a lower alkyl group, a hydroxy group, an alkoxy group, an acyl group, an acyloxy group, an alkoxycarbonyl group, a nitro group, an amino group, a substituted amino group, a carbamoyl group or an alkylcarbamoyl group, and n is an integer of from 2 to 6; and xcex1 represents the following formula (a), (b), (c), (d) or (e): 
wherein
in formulae (a) and (b), R3 represents a hydrogen atom, a halogen atom, a lower alkyl group, a hydroxy group or an alkoxy group, X represents NR10, NCONR11R12, S, SO, SO2 or O, R10 represents a hydrogen atom, a lower alkyl group, an alkenyl group, an oxoalkyl group, an aralkyl group, a cyanoalkyl group, a hydroxyalkyl group, an alkoxyalkyl group, an aminoalkyl group, a substituted aminoalkyl group, an alkoxycarbonylalkyl group, a carbamoylalkyl group, an alkylcarbamoylalkyl group, an acyl group or an alkoxycarbonyl, R11 and R12 independently represent a hydrogen atom or a lower alkyl group, and Y represents a methylene group or a carbonyl group,
in formula (c), R4 represents a hydrogen atom, a halogen atom, a lower alkyl group, a hydroxy group, a cyano group, a trihalomethyl group, an alkoxy group, an alkylthio group, an alkylsulfinyl group, an alkylsulfonyl group, an alkoxycarbonyl, a sulfamoyl group, an amino group, a substituted amino group, a carbamoyl group, an alkylcarbamoyl group, an acyl group or a carboxy group, R5 represents a hydrogen atom, a lower alkyl group, a hydroxy group, an alkoxy group, an acyl group, a phenyl group or a substituted phenyl group, k is 0 or an integer of from 1 to 3, m is 0 or an integer of from 1 to 3, and each of A and B represents a group which forms a benzene ring, a thiophene ring, a furan ring, an imidazole ring or a pyrazole ring via a double bond, with the proviso that k+m is an integer of from 1 to 3, and
in formulae (d) and (e), R4 is as defined in the foregoing, G represents CH2, S, O or Cxe2x95x90O, D represents CH or N, p is an integer of from 1 to 3, each of E and J represents a group which forms a benzene ring or a pyridine ring via a double bond, and R6 and R7 independently represent a hydrogen atom, a lower alkyl group, a hydroxy group, an alkoxy group, an acyl group, a phenyl group or a substituted phenyl group or a pharmaceutically acceptable salt thereof.
2. A compound according to the aforementioned item 1, which is represented by formula (1a): 
wherein R2, R3, X and n are as defined in the foregoing, or a pharmaceutically acceptable salt thereof.
3. A compound according to the aforementioned item 2, which is represented by formula (1a-1): 
wherein X and n are as defined in the foregoing, or a pharmaceutically acceptable salt thereof.
4. A compound according to the aforementioned item 1, which is represented by formula (1b): 
wherein R2, R3, X, Y and n are as defined in the foregoing, or a pharmaceutically acceptable salt thereof.
5. A compound according to the aforementioned item 4, which is represented by formula (1b-1): 
wherein X, Y and n are as defined in the foregoing, or a pharmaceutically acceptable salt thereof.
6. A compound according to the aforementioned item 1, which is represented by formula (1c): 
wherein R1, R4, R5, A, B, k, m and n are as defined in the foregoing, or a pharmaceutically acceptable salt thereof.
7. The compound or a pharmceutically acceptable salt thereof according to the aforementioned item 6, wherein k+m is 2.
8. The compound or a pharmaceutically acceptable salt thereof according to the aforementioned item 6 or 7, wherein n is 4.
9. A compound according to claim 1, which is represented by formula (1d): 
wherein R4, G, D, E, J, p and n are as defined in the foregoing, or a pharmaceutically acceptable salt thereof.
10. A compound according to the aforementioned item 1, which is represented by formula (1e): 
wherein R4, R6, R7, D and n are as defined in the foregoing, or a pharmaceutically acceptable salt thereof.
11. A pharmaceutical composition which comprises any one of the compounds of the aforementioned items 1 to 10 or a pharmaceutically acceptable salt thereof.
12. A pharmaceutical composition for treatment or prevention of mental diseases, which comprises any one of the compounds of the aforementioned items 1 to 10 or a pharmaceutically acceptable salt thereof.
13. A compound represented by formula (aQ): 
wherein Z represents NR13, NCONR11R12, SO or SO2, R13 represents a carbamoylalkyl group, an alkylcarbamoylalkyl group, an alkenyl group or an oxoalkyl group, R11 and R12 independently represent a hydrogen atom or a lower alkyl group, Q represents a hydrogen atom or a protecting group and R3 is as defined in the foregoing, or a salt thereof.
14. A compound represented by formula (bQ): 
wherein R3, Y, Z and Q are as defined in the foregoing, or a salt thereof.
In the descriptions of this specification concerning the chemical substances and production methods thereof, the term halogen atom means each atom of fluorine, chlorine, bromine and iodine, the term lower alkyl means methyl, ethyl or the like straight chain alkyl having from 1 to 4 carbon atoms and isopropyl, isobutyl, t-butyl or the like branched-chain alkyl or a halogen-substituted compound thereof, and the term base to be used as a catalyst means sodium hydroxide, potassium carbonate, triethylamine or the like. In addition, the term substituent group means a group other than hydrogen atom.
In the formula (1), each symbol has the following meaning;
R1 represents hydrogen atom, lower alkyl or aralkyl,
R2 represents hydrogen atom, halogen atom, lower alkyl, hydroxy, alkoxy (preferably having from 1 to 4 carbon atoms, such as methoxy or ethoxy), acyl (preferably having from 1 to 4 carbon atoms), acyloxy (preferably having from 1 to 4 carbon atoms), alkoxycarbonyl (the alkyl moiety preferably having from 1 to 4 carbon atoms), nitro, amino, substituted amino (preferably, amino substituted by lower alkyl, such as dimethylamino or diethylamino), carbamoyl or alkylcarbamoyl (the alkyl moiety preferably having from 1 to 4 carbon atoms), and n is an integer of from 2 to 6.
In the formulae (a) and (b)
R3 represents hydrogen atom, halogen atom, lower alkyl, hydroxy or alkoxy (preferably having from 1 to 4 carbon atoms, such as methoxy or ethoxy), X represents NR10, NCONR11R12, S, SO, SO2 or O, R10 represents hydrogen atom, lower alkyl, alkenyl (preferably having from 1 to 4 carbon atoms), oxoalkyl (preferably having from 1 to 4 carbon atoms), aralkyl, cyanoalkyl (the alkyl moiety preferably having from 1 to 4 carbon atoms), hydroxyalkyl (preferably having from 1 to 4 carbon atoms), alkoxyalkyl (each alkyl moiety preferably having from 1 to 4 carbon atoms), aminoalkyl (preferably having from 1 to 4 carbon atoms), substituted aminoalkyl (preferably an alkylaminoalkyl in which each alkyl moiety has from 1 to 4 carbon atoms, such as dimethylaminoethyl), alkoxycarbonylalkyl (each alkyl moiety preferably having from 1 to 4 carbon atoms), carbamoylalkyl (the alkyl moiety preferably having from 1 to 4 carbon atoms, such as carbamoylmethyl or carbamoylethyl), alkylcarbamoylalkyl (each alkyl moiety preferably having from 1 to 4 carbon atoms), acyl (preferably having from 1 to 4 carbon atoms) or alkoxycarbonyl (the alkyl moiety preferably having from 1 to 4 carbon atoms, such as methoxycarbonyl or ethoxycarbonyl), R11 and R12 independently represent hydrogen atom or lower alkyl, and Y represents methylene or carbonyl.
In the compounds represented by the formula (aQ) or (bQ), which are novel intermediates among compounds in which the free valency N of the group represented by the formula (a) or (b) is substituted with Q (represents hydrogen atom or a protecting group), R3 represents hydrogen atom, halogen atom, lower alkyl, hydroxy or alkoxy (preferably having from 1 to 4 carbon atoms, such as methoxy or ethoxy), Z represents NR13, NCONR11R12, SO or SO2, R13 represents carbamoylalkyl (the alkyl moiety preferably having from 1 to 4 carbon atoms, such as carbamoylmethyl or carbamoylethyl), alkylcarbamoylalkyl (each alkyl moiety preferably having from 1 to 4 carbon atoms), alkenyl (preferably having from 1 to 4 carbon atoms, such as allyl) or oxoalkyl (preferably having from 1 to 4 carbon atoms, such as 2-oxo-propyl), and R11 and R12 independently represent hydrogen atom or lower alkyl.
In the formula (c),
R4 represents hydrogen atom, halogen atom, lower alkyl, hydroxy, cyano, trihalomethyl (wherein the halogen atom is as defined in the foregoing and the three halogen atoms may be the same or different from one another, preferably trifluoromethyl or the like), alkoxy (preferably having from 1 to 4 carbon atoms, such as methoxy or ethoxy), alkylthio (preferably having from 1 to 4 carbon atoms, such as methylthio or ethylthio), alkylsulfinyl (preferably having from 1 to 4 carbon atoms), alkylsulfonyl (preferably having from 1 to 4 carbon atoms), alkoxycarbonyl (the alkyl moiety preferably having from 1 to 4 carbon atoms), sulfamoyl, amino, substituted amino (preferably amino substituted by lower alkyl, such as dimethylamino or diethylamino), carbamoyl, alkylcarbamoyl (preferably the alkyl moiety is lower alkyl, such as dimethylcarbamoyl), acyl (preferably having from 1 to 4 carbon atoms, such as acetyl) or carboxy,
R5 represents hydrogen atom, lower alkyl, hydroxy, alkoxy (preferably having from 1 to 4 carbon atoms, such as methoxy or ethoxy) acyl (preferably having from 1 to 4 carbon atoms, such as acetyl), phenyl or substituted phenyl, and
k is 0 or an integer of from 1 to 3, m is 0 or an integer of from 1 to 3, with the proviso that k+m is an integer of from 1 to 3. Namely, the nitrogen atom binding to the methylene chain forms a five- to seven-membered ring, preferably a six-membered ring, and the nitrogen-containing hetero ring is condensed, via its double bond, with benzene ring, thiophene ring, furan ring, imidazole ring or pyrazole ring formed by A and B, so that the formula (c) as a whole represents indolinyl, tetrahydroquinolyl, tetrahydro isoquinolyl, 2,3,4,5-tetrahydro-3H-benzo[b]azepinyl, 2,3,4,5-tetrahydro-1H-benzo[c]azepinyl, 2,3,4,5-tetrahydro-1H-benzo[d]azepinyl, 4,5,6,7-tetrahydrothieno[3,2-c]pyridyl, 4,5,6,7-tetrahydrofuro[3,2-c]pyridyl, 4,5,6,7-tetrahydropyrazolo[4,3-c]pyridyl and the like. Preferably, n is 4.
In the formulae (d) and (e),
R4 is as defined in the aforementioned formula (c) and similar group is desirable, G represents CH2, S, O or Cxe2x95x90O, D represents CH or N, p is an integer of from 1 to 3, each of E and J represents a group which forms benzene ring or pyridine ring via a double bond, and R6 and R7 independently represent hydrogen atom, lower alkyl, hydroxy, alkoxy (preferably having from 1 to 4 carbon atoms, such as methoxy or ethoxy), acyl (preferably acetyl or the like), phenyl or substituted phenyl (preferably phenyl substituted by halogen, such as chlorophenyl or bromophenyl).
In this connection, in the formula (1), R2, R3, R4 or R5 is a symbol which can represent all hydrogen atoms on the ring, and when R2, R3, R4 or R5 is a substituent group, it can be substituted on any hydrogen atom on the ring independently, so that there will be no substitution or one or more positions will be substituted by the same or different groups.
The compounds provided by the invention are produced by the chemical synthesis methods described in the following.
The compound represented by the formula (1) (to be referred to as xe2x80x9ccompound (1) of the inventionxe2x80x9d hereinafter) can be obtained by allowing a compound represented by a formula (5) [in the formula, xcex1 is as defined in the foregoing] or a salt thereof prepared in advance to react with a compound represented by a formula (4) [in the formula, W is a halogen atom, an alkylsulfonic ester residue such as methanesulfonyloxy or ethanesulfonyloxy or an arylsulfonic acid ester residue such as benzenesulfonyloxy or p-toluenesulfonyloxy, and R1, R2 and n are as defined in the foregoing] (to be referred to as xe2x80x9ccompound (4)xe2x80x9d hereinafter, the compounds represented by other formulae are also expressed in the same manner) prepared in advance (reaction formula 1). 
The above reaction is carried out in the presence or absence of a base without solvent or after dilution with an inert solvent at a temperature within the range of from ordinary temperature to heating temperature. Examples of the inert solvent to be used include dioxane, tetrahydrofuran, acetone, methyl ethyl ketone, acetonitrile, dimethylformamide and the like, and examples of the base to be used include salts of alkali metals, such as sodium carbonate, potassium carbonate and the like carbonates and sodium bicarbonate, potassium bicarbonate and the like bicarbonates, and trialkylamines, pyridine bases and the like.
The aforementioned compounds (1a), (1a-1), (1b), (1b-1), (1c), (1d) and (1e) can be produced by appropriately selecting respective substituent groups of the above compounds (4) and (5).
When R1 is hydrogen atom in the compound (4) of the aforementioned reaction formula 1, a compound (4-2) is obtained by carrying out substitution reaction of respective aromatic ring of an organic synthesis material 2a,3,4,5-tetrahydrobenz[cd]indol-2-(1H)one [compound (2-1)] to obtain a compound (2-2) which is then allowed to react with a compound (3) [in the formula (3), W and n are as defined in the foregoing], or the compound (4-2) can be obtained by carrying out substitution reaction of respective aromatic ring of a compound (4-1) derived from the compounds (2-1) and (3) (reaction formula 2). In addition, the substituent group introduced on the aromatic ring may be converted into other substituent group by a chemical reaction before or after its reaction with the compound (5). 
Also, when R1 is a lower alkyl or an aralkyl, the following reaction step can be used.
Benz[cd]indol-2 (1H) one [compound (2-0)] is used as the starting material and allowed to react with a compound (6) [in the formula (6), W is as defined in the foregoing, and R is a lower alkyl group or an aralkyl group] in the presence of a base to obtain a compound (2-0-1), 
and then the compound (2-0-1) is allowed to undergo the reaction in an atmosphere of hydrogen using Raney nickel as a catalyst to obtain a compound (2-3). 
When the compound (2-3) is used instead of the compound (2-1) in the above reaction formula 2, a compound (4-3) in which R1 in the compound (4) is R or a compound (4-4) in which R2 is a substituent group can be obtained (reaction formula 3) 
Also, it is possible to carry out synthesis of the compound (1) of the invention using the following compound (4-5) instead of the compound (4) in the aforementioned reaction formula 1.
The compound (4-5) is synthesized using an alkene represented by CH2xe2x95x90CHxe2x80x94(CH2)nxe2x88x921xe2x80x94W [wherein n and W are as defined in the foregoing] or xe2x80x94(CH2)nxe2x88x921xe2x80x94W [wherein q is protected hydroxyl group, and n and W are as defined in the foregoing] instead of the compound (3) in the aforementioned reaction formula 2 or 3. 
The compound (2-1-4) is allowed to react with CH2xe2x95x90CHxe2x80x94(CH2)nxe2x88x921xe2x80x94W or qxe2x80x94(CH2)nxe2x80x94W in the presence of a base and then converted into an aldehyde compound by allowing the alkene to react with osmium tetroxide and sodium periodate, or converted into an aldehyde compound represented by the compound (4-5) by, for example, carrying out deprotection and oxidation of q, and the desired compound (1) can be obtained by carrying out reductive aminoalkylation reaction of the aldehyde compound with a secondary amine represented by the compound (5) using sodium triacetoxyborohydride.
It is desirable to introduce the substituent group R2 into aromatic ring by a generally known aromatic electrophilic substitution reaction. Examples of the aromatic electrophilic substitution reaction include halogenation, Friedel-Crafts"" reaction-based alkylation and acylation and nitration.
In a preferred example of the halogenation, the reaction is carried out at a temperature of from 0xc2x0 C. to reflux temperature in carbon disulfide, carbon tetrachloride, chloroform, dichloromethane, 1,2-dichloroethane, acetic acid, water or the like solvent in the presence or absence of an appropriate catalyst. Examples of the halogenation agent to be used include fluorine, chlorine, bromine and iodine, as well as 1-fluoropyridinium trifurate, 1-fluoro-2,6-dichloropyridinium tetrafluoroborate and the like unsubstituted or substituted N-fluoropyridinium salts, N-fluoro-N-propyl-p-toluenesulfonamide and the like N-fluoro-N-alkyl-sulfonamides, N-fluorobenzenesulfonimide and the like N-fluorosulfonimides, sodium hypochlorite, N-bromosuccinimide and the like.
The Friedel-Crafts"" reaction is carried out at a temperature of from 0xc2x0 C. to reflux temperature in carbon disulfide, chloroform, dichloromethane, 1,2-dichloroethane, nitrobenzene or the like solvent in the presence of a catalyst. Examples of the alkylation agent to be used include halogenated hydrocarbons, as well as methanol, ethanol and the like alcohols and propene and the like olefin compounds. Examples of the acylation agent to be used include acetyl chloride, propyl chloride and the like acyl halides, as well as acetic anhydride and the like acid anhydrides and acetic acid, propionic acid and the like carboxylic acids. Alternatively, an acid chloride derivative is obtained using oxalic acid chloride, triphosgene or the like and then hydrolyzed using water, alcohol, amines and the like to convert it into respective carboxylic acid derivative, ester derivative and amide derivative. Examples of the catalyst to be used desirably include aluminum chloride, iron chloride, boron trifluoride, tin chloride, zinc chloride and the like Lewis acids, as well as hydrogen fluoride, sulfuric acid, polyphosphoric acid and the like proton acids.
In an example of the nitration, the reaction is carried out using concentrated nitric acid and concentrated sulfuric acid or using nitric acid in water, acetic acid or acetic anhydride solution. In addition, ethyl nitrate and the like nitric acid esters, acetyl nitrate and the like mixed acids and nitronium tetrafluoroborate and the like nitronium salts can also be used.
As occasion demands, the substituent group R2 introduced into the aromatic ring may be converted into other substituent group by a chemical reaction. The reaction may be carried out either before the reaction with the compound (5) or after completion of the reaction with the compound (5) in the reaction formula 1, with the proviso that it does not exert influence upon other functional groups, structures and the like. For example, acetyl group or the like acyl group can be converted into corresponding acyloxy group by allowing it to react with m-chloroperbenzoic acid, pertrifluoroacetic acid or the like peroxide in the presence of trifluoroacetic acid or the like acid catalyst as occasion demands, thereby effecting insertion of oxygen atom between the aromatic ring and carbonyl group. Thereafter, the acyloxy group can be converted into alkoxy group by removing the acyl group through hydrolysis or the like method and then allowing it to react with methyl iodide or the like alkylation agent in the presence of potassium carbonate, sodium bicarbonate or the like base. Also, methoxycarbonyl group or the like ester group can be converted into a carbamoyl derivative, an amide derivative or the like, when it is allowed to react, directly or after its hydrolysis into carboxylic acid, with ammonia, a primary amine, a secondary amine or the like via an active ester or the like reactive derivative.
In the aforementioned reaction formula 2, the compound (3) belongs to a so-called reaction intermediate and is generally available as a synthetic reagent or synthesized from diols represented by a formula HOxe2x80x94(CH2)n13 OH [wherein n is as defined in the foregoing]. That is, a diol is obtained as a dihalide by allowing it to react with thionyl chloride or thionyl bromide or as a disulfonate by allowing it to react with methanesulfonyl chloride or the like alkylsulfonic acid halide or benzenesulfonyl chloride or the like arylsulfonic acid halide. As another example of the halogenation reaction, halogenation using carbon tetrachloride or carbon tetrabromide in the presence of triphenylphosphine can also be used.
Next, the compound (5) (xcex1-H) shown in the aforementioned reaction formula 1 is described.
The compound (5) is any one of the groups (a) to (e) in which hydrogen atom is substituted on the N having free valency.
In the following, a compound in which hydrogen atom is substituted on the free valency N of the group (a) is called compound (aH). In the same manner, compounds in which hydrogen atom is substituted on the free valency N of the groups (b) to (e) are called compounds (bH) to (eH).
Compound (aH) is described.
When X represents either NR10 or NCONR11R12, the compound can be derived using commercially available 2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indoles or from a commercially available tryptamine derivative and formaldehyde by, for example, the Pictet-Spengler reaction (e.g., Organic Reactions, 6, 151, 1951). Also, 9-position-modified products of 2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, derived from them by various chemical reactions, may be used. Their examples include 9-alkyl derivatives, 9-acyl derivatives, 9-carbamoyl derivatives, 9-alkoxycarbonyl derivatives and the like.
The aforementioned 9-position-modified products of 2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole can be obtained by protecting the 2-position secondary amino group of 2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indoles with a generally used protecting group, carrying out alkylation, acylation or the like chemical reaction and then effecting deprotection. It is desirable that the protecting group to be used is stable under alkylation, acylation and the like chemical reaction conditions and can be deprotected easily, and its examples include t-butoxycarbonyl group, benzyloxycarbonyl group or the like carbamate, as well as benzyl group and the like.
As an example of the synthesis of the aforementioned 9-position-modified product of 2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, it is desirable to carry out the reaction of a 2-position amino group-protected 2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole derivative within the range of from low to heating temperature in the presence of sodium hydride, n-butyl lithium, lithium diisopropylamide or the like strong base, after its dilution with tetrahydrofuran, diethyl ether, toluene, 1,2-dimethoxyethane, dimethylformamide, dimethyl sulfoxide or the like inert solvent. Examples of the alkylation agent to be used include methyl iodide, ethyl bromide, allyl bromide or the like straight chain alkyl halide or straight chain alkenyl halide and isopropyl bromide, isobutyl bromide or the like branched-chain alkyl halide, as well as chloromethyl methyl ether, bromoacetonitrile, benzyl bromide, bromoacetamide, methyl bromoacetate, 2-chloro-N,N-dimethylethylamine and the like, and examples of the acylation agent to be used include acetyl chloride, propionyl chloride, isobutyryl chloride or the like acyl halide, as well as dimethylcarbamoyl chloride, diethylcarbamoyl chloride, methyl chloroformate, ethyl chloroformate and the like.
In addition, the 9-carbamoyl derivative and 9-alkoxycarbonyl derivative of 2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole can also be synthesized by subjecting the compound to chloroformylation with triphosgene and then allowing it to react with ammonia, methylamine and the like amines or methanol, ethanol and the like alcohols, in tetrahydrofuran, diethyl ether, toluene, 1,2-dimethoxyethane, dimethylformamide, dimethyl sulfoxide or the like inert solvent in the presence of sodium hydride, n-butyl lithium, lithium diisopropylamide or the like strong base.
Also, when X is any one of S, SO, SO2 and O, the compound (aH) can be synthesized by a generally known method. For example, 3,4-dihydro-1H-benzo[4,5]thieno[2,3-c]pyridine can be synthesized via cyclization, amidation, amide reduction and Pictet-Spengler cyclization of 4-(phenylthio)acetoacetic acid ethyl ester which is obtained from substituted or unsubstituted thiophenol and 4-chloroacetoacetic acid ethyl ester (J. Heterocyclic Chem., 16, 1321, 1979). In addition, it can be converted into a sulfoxide derivative or a sulfone derivative by oxidizing the 9-position sulfur atom. For example, 3,4-dihydro-9-oxo-9-xcex4-1H-benzo[4,5]thieno[2,3-c]pyridine or 3,4-dihydro-9,9-dioxo-9-xcex6-1H-benzo[4,5]thieno[2,3-c]pyridine can be obtained by protecting the 2-position amino group of 3,4-dihydro-1H-benzo[4,5]thieno[2,3-c]pyridine with t-butoxycarbonyl group, benzyloxycarbonyl group or the like protecting group, and then deprotecting the sulfur atom by its selective oxidation with m-chloroperbenzoic acid or hydrogen peroxide. On the other hand, 3,4-dihydro-1H-benzo[4,5]furo[2,3-c]pyridine can be synthesized, for example, via nitrile reduction, formamidation, cyclization and imine reduction of 3-cyanomethylbenzo[b]furan which is obtained from 3-(2H)-benzo[b]furanone and diethylcyanomethyl phosphate (JP-A-63-22581; the term xe2x80x9cJP-Axe2x80x9d as used herein means an xe2x80x9cunexamined published Japanese patent applicationxe2x80x9d).
The compound (aQ) (Q is hydrogen atom or a protecting group) as a novel intermediate for the production of the compound (1) of the invention is a case in which the aforementioned X is Z and can be synthesized in the same manner as described above.
Next, the compound (bH) is described.
When X is O and Y is methylene, this can be synthesized by a generally known method. That is, as shown in the reaction formula 4, the primary amino group of a benzoxazine derivative (7) (Gupta, S. P. et al., Synthesis, 9, 660, 1974) is protected with benzyloxycarbonyl group or the like appropriate protecting group (Q) to obtain a compound (8), and then a compound (bH-1) can be synthesized via a chloroacetylated derivative (9), its cyclization to a pyrazinobenzoxazine derivative (10), a compound (11) by amide reduction and removal of the protecting group (Q) (E. W. Baxter et al., Bioorg. Med. Chem. Lett., 7, 763, 1997).
Also, when X is any one of S, SO and SO and Y is methylene, 1,2,3,4,4a,5-hexahydropyrazino[2,1-c]-1,4-benzthiazine can be synthesized in accordance with the method shown in the reaction formula 4 from a generally known compound 3,4-dihydro-3-aminomethyl-2H-1,4-benzthiazine (P. Melloni et al., J. Heterocyclic Chem., 20, 139, 1983), and a sulfoxide derivative and a sulfone derivative of the compound (bH) can be obtained by deprotecting the 6-position sulfur atom of the compound (11) through its selective oxidation with m-chloroperbenzoic acid or hydrogen peroxide. 
Also, when X is either NR10 or NCONR11R12 and Y is carbonyl or methylene, the compound (bH) can be synthesized from a generally known compound 2,3,4,4a-tetrahydro-1H-pyrazino[1,2-a]quinoxalin-5(6H)-one derivative or 2,3,4 ,4a,5,6-hexahydro-1H-pyrazino[1,2-a]quinoxaline derivative (JP-A-52-114000) by carrying out alkylation, acylation or the like chemical modification. For example, an alkyl group can be introduced to the amido nitrogen by allowing a compound in which the 3-position of 2,3,4,4a-tetrahydro-1H-pyrazino[1,2-a]quinoxalin-5(6H)-one is protected with benzyloxycarbonyl group or the like appropriate protecting group to react with methyl iodide, ethyl bromide or the like alkylation agent in the presence of sodium hydride or the like base. Also, the compound (bH) as a 6-position-modified product can be obtained by allowing a compound in which the 3-position of 2,3,4,4a,5,6-hexahydro-1H-pyrazino[1,2-a]quinoxaline is protected with benzyloxycarbonyl group or the like appropriate protecting group to react with acetyl chloride, propionyl chloride, isobutyryl chloride or the like acyl halide and trifluoroacetic acid anhydride, dimethylcarbamoyl chloride, diethylcarbamoyl chloride, methyl chloroformate, ethyl chloroformate or the like acylation agent, in the presence of triethylamine or the like base.
The compound (bQ) (Q is hydrogen atom or a protecting group) as a novel intermediate for the production of the compound (1) of the invention is a case in which the aforementioned X is Z and can be synthesized in the same manner as described above.
Next, the method for synthesizing the compound (cH) which is an intermediate for the production of the compound (1) of the invention is described in detail.
When benzene ring is formed by a carbon-carbon double bond of the nitrogen-containing hetero ring and the groups A and B which bind to its constituting carbon atoms, and also when k+m is 3, it can be derived from a generally known compound 2,3,4,5-tetrahydro-benzo[c]azepin-1-one or 1,3,4,5-tetrahydro-benzo[b]azepin-2-one [Tetrahedron, 49, 1807, 1993].
Also, when thiophene ring is formed by a carbon-carbon double bond of the nitrogen-containing hetero ring and the groups A and B which bind to its constituting carbon atoms, various derivatives of the compound (cH) can be synthesized from a generally known compound 4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxylic acid [JP-A-5-60836], 4,5,6,7-tetrahydrothieno[2,3-c]pyridine-2-carboxylic acid, 5,6,7,8-tetrahydro-4H-thieno[3,2-c]azepine-2-carboxylic acid or 5,6,7, 8-tetrahydro-4H-thieno[2,3-c]azepine-2-carboxylic acid [WO 94/21599].
Also, when furan ring is formed by a carbon-carbon double bond of the nitrogen-containing hetero ring and the groups A and B which bind to its constituting carbon atoms, various derivatives of the compound (cH) can be synthesized from a generally known compound such as 4,5,6,7-tetrahydrofuro[3,2-c]pyridine, 4,5,6,7-tetrahydrofuro[2,3-c]pyridine, 5,6,7,8-tetrahydro-4H-furo[2,3-c]azepine or 5,6,7,8-tetrahydro-4H-furo[2,3-d]azepine [JP-A-9-118681].
Also, when pyrazole ring is formed by a carbon-carbon double bond of the nitrogen-containing hetero ring and the groups A and B which bind to its constituting carbon atoms, and also when k is 0, it can be synthesized by a generally known method. That is, as shown in the following reaction formula 5, the compound (cH-1) (a compound in which Q1 of the compound (cQ-1) is H) can be synthesized by firstly obtaining a compound (13) by allowing a protected keto-cyclic amine (12) [wherein Q1 is benzyl or the like protecting group, and m is an integer of from 1 to 3] to react with excess amount of an N,N-dialkylformamidodimethylacetal derivative generally at from 50xc2x0 C. to 150xc2x0 C. for a period of from 30 minutes to 10 hours, subsequently obtaining the compound (cQ-1) by condensing the compound (13) with from 1 to 5 equivalents of hydrazine or a lower alkylhydrazine generally at from 20xc2x0 C. to 100xc2x0 C. for from 10 minutes to 30 hours using methanol or the like lower alcohol as the solvent, and then removing the protecting group [JP-A-6-73056]. 
In the above synthesis method of the compound (cH), the substituent groups R4 and R5 of the compound (cH) can be optionally selected from those which are present on the ring of a compound to be used as the material, with the proviso that they do not hinder the above reactions, and these substituent groups can be substituted after synthesis of the compound (cH). Their typical examples include, as R4, halogen atom, lower alkyl, hydroxy, cyano, trihalomethyl (wherein the halogen atom is as defined in the foregoing and the three halogen atoms may be the same or different from one another, preferably trifluoromethyl or the like), alkoxy (preferably having from 1 to 4 carbon atoms, such as methoxy or ethoxy), alkylthio (preferably having from 1 to 4 carbon atoms, such as methylthio or ethylthio), alkylsulfinyl (preferably having from 1 to 4 carbon atoms), alkylsulfonyl (preferably having from 1 to 4 carbon atoms), alkoxycarbonyl (the alkyl moiety preferably having from 1 to 4 carbon atoms), sulfamoyl, amino, substituted amino (preferably amino substituted by lower alkyl, such as dimethylamino or diethylamino), carbamoyl, alkylcarbamoyl (preferably the alkyl moiety is lower alkyl, such as dimethylcarbamoyl), acyl (preferably having from 1 to 4 carbon atoms, such as acetyl) and carboxy, and as R5, hydrogen atom, lower alkyl, hydroxy, alkoxy (preferably having from 1 to 4 carbon atoms, such as methoxy or ethoxy), acyl (preferably having from 1 to 4 carbon atoms, such as acetyl), phenyl and substituted phenyl.
The secondary amines represented by the compound (cH) are shown below more illustratively;
indoline,
2-methylindoline,
2,3-dimethylindoline,
1,2,3,4-tetrahydroquinoline,
6-fluoro-1,2,3,4-tetrahydro-2-methylquinoline,
1,2,3,4-tetrahydroisoquinoline,
6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline,
6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline,
6,7-dihydroxy-1,2,3,4-tetrahydro-1-methylisoquinoline,
1-[5-chloro-2-(methylamino)-phenyl]-1,2,3,4-tetrahydroisoquinoline,
2,3,4,5-tetrahydro-1H-benzo[b]azepine,
2,3,4,5-tetrahydro-1H-benzo[c]azepine,
5-phenyl-2,3,4,5-tetrahydro-1H-benzo[c]azepine,
4,5,6,7-tetrahydrothieno[3,2-c]pyridine,
4,5,6,7-tetrahydrothieno[2,3-c]pyridine,
2-methyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine,
3-methyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine,
2,3-dimethyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine,
4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxylic acid,
4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxylic acid methyl ester,
2-carbamoyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine,
2-dimethylcarbamoyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine,
4,5,6,7-tetrahydrofuro[3,2-c]pyridine,
4,5,6,7-tetrahydrofuro[2,3-c]pyridine,
4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine,
4,5,6,7-tetrahydro-2-methyl-2H-pyrazolo[4,3-c]pyridine,
4,5,6,7-tetrahydro-3-methyl-1H-pyrazolo[4,3-c]pyridine,
4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridine and the like.
Next, methods for the synthesis of the compounds (dH) and (eH) as intermediates for the production of the compound (1) of the invention are described in detail.
Regarding the compound (dH), ketone of a corresponding compound (14) [wherein R4, G, E, J and p are as defined in the foregoing] is converted into alcohol form of a compound (15) by reducing it with sodium borohydride (reaction formula 6). 
Next, the compound (15) is converted into a compound (16) by its chlorination using thionyl chloride (reaction formula 7). 
The compound (16) is condensed with a compound (17) N-t-butoxycarbonylpiperazine in the presence of a base to obtain a compound (18) (reaction formula 8). 
By further subjecting the compound (18) to de-t-butoxycarbonylation under an acidic condition, a compound (dH-1) is synthesized (reaction formula 9). 
As another example of the synthesis of the compound (dH), firstly, 4-bromopyridine as a compound (19) is allowed to react with the corresponding ketone compound (14) in ether using n-butyl lithium to obtain a compound (20) (reaction formula 10). 
By reducing the compound (20) in an atmosphere of hydrogen using platinum oxide as a catalyst, a compound (dH-2) is synthesized (reaction formula 11). 
Regarding the compound (eH), a compound (21) [wherein y is a halogen atom, and R4, R6 and R7 are as defined in the foregoing] is condensed with the compound (17) N-t-butoxycarbonylpiperazine in the presence of a base to obtain a compound (22). 
By further subjecting the compound (22) to de-t-butoxycarbonylation under an acidic condition, a compound (eH-1) is synthesized (reaction formula 13). 
As another example of the synthesis of the compound (eH), firstly, 4-bromopyridine as the compound (19) is allowed to react with a corresponding ketone represented by a compound (23) [wherein R4 is as defined in the foregoing, and R8 is lower alkyl, phenyl or substituted phenyl group] in ether using n-butyl lithium to obtain a compound (24) (reaction formula 14). 
By reducing the compound (24) in an atmosphere of hydrogen using platinum oxide as a catalyst, a compound (eH-2) is synthesized (reaction formula 15). 
By further reducing the compound (eH-2) in an atmosphere of hydrogen using palladium-carbon as a catalyst, a compound (eH-3) is synthesized (reaction formula 16). 
As shown in the aforementioned reaction formula 6, the compound (14) can be converted into the compound (15) using sodium borohydride. This reaction is generally carried out after dilution with an alcohol or water and progresses within the range of from ordinary temperature to heating. Examples of the alcohol to be used include methanol, ethanol and the like.
As shown in the aforementioned reaction formula 7, the compound (16) is obtained by chlorinating the compound (15) using thionyl chloride. This reaction is carried out without solvent or by diluting with a chlorinated solvent or an aromatic solvent. Examples of the solvent to be used include dichloromethane or chloroform as the chlorinated solvent and benzene, toluene or the like as the aromatic solvent.
As shown in the aforementioned reaction formulae 8 and 12, the compound (16) or (21) is converted into the desired compound (18) or (22) by carrying out its reaction with the compound (17), N-t-butoxycarbonylpiperazine. This reaction is carried out without solvent or after dilution with an inert solvent and progresses in the presence or absence of a base, in the presence or absence of a catalytically effective amount of potassium iodide or sodium iodide and within the range of from ordinary temperature to heating temperature. Examples of the inert solvent to be used include dioxane, tetrahydrofuran, acetonitrile, dimethylformamide, methyl ethyl ketone and the like, and examples of the base to be used include salts of alkali metals, such as sodium carbonate, potassium carbonate and the like carbonates and sodium bicarbonate, potassium bicarbonate and the like bicarbonates, and trialkylamines, pyridine bases and the like, or the secondary amine itself to be used as the material substance may also serve as the base when used in an excess amount.
As shown in the aforementioned reaction formulae 9 and 13, the compound (18) or (22) can be converted into the compound (dH-1) or (eH-1) by removing the t-butoxycarbonyl group under an acidic condition. Examples of the acid to be used include hydrochloric acid, trifluoroacetic acid and the like. As shown in the aforementioned reaction formulae 10 and 14, the compound (19) can be converted into the compound (20) or (24) by allowing it to react with the compound (14) or (23) using n-butyl lithium. The reaction is carried out after dilution with an ether solvent and progresses within the range of from xe2x88x9278xc2x0 C. to room temperature. Examples of the ether solvent to be used include diethyl ether, tetrahydrofuran, dimethoxyethane and the like.
As shown in the aforementioned reaction formulae 11 and 15, the compound (20) or (24) can be converted into the compound (dH-2) or (eH-2) by its catalytic hydrogen reduction in the presence of platinum oxide. As shown in the aforementioned reaction formula 16, the compound (eH-3) is obtained from the compound (eH-2) by its catalytic hydrogen reduction in the presence of Pd-C.
These reactions are carried out after dilution with a polar solvent or a non-polar solvent and progress under ordinary pressure or under compression. Examples of the solvent to be used include water, an alcohol or acetic acid as the polar solvent and ether, benzene, hexane or the like as the non-polar solvent.
In the aforementioned synthesis method of the compound (dH) or (eH), the substituent groups R4, R6 and R7 can be optionally selected from those which are present on the benzene and pyridine ring of the compound (14), (21) or (23) to be used as the material, with the proviso that they do not hinder the above reactions.
The compound (14) as the synthesis material ketones of the compound (dH) is shown below more illustratively;
1-indanone,
6-methyl-1-indanone,
4-methyl-1-indanone,
5-fluoro-1-indanone,
5-chloro-1-indanone,
5-bromo-1-indanone,
4-hydroxy-1-indanone,
4-methoxy-1-indanone,
5-methoxy-1-indanone,
6-methoxy-1-indanone,
xcex1-tetralone,
5-hydroxy-1-tetralone,
5-methoxy-1-tetralone,
6-methoxy-1-tetralone,
7-methoxy-1-tetralone,
1-benzosuberone,
8-fluoro-1-benzosuberone,
4-chromanone,
thiochromanone-4-one,
6-fluoro-4-chromanone,
6-methyl-4-chromanone,
6-chloro-4-chromanone.
The compound (21) as the synthesis material halides of the compound (eH) is shown below more illustratively;
benzyl chloride,
benzyl bromide,
(1-bromoethyl)benzene,
2-fluorobenzyl chloride,
2-chlorobenzyl chloride,
2-chlorobenzyl bromide,
2-bromobenzyl bromide,
2-methylbenzyl bromide,
2-methylbenzyl chloride,
3-fluorobenzyl chloride,
4-fluorobenzyl bromide,
4-fluorobenzyl chloride,
3-fluorobenzyl bromide,
3-chlorobenzyl chloride,
4-chlorobenzyl chloride,
3-chlorobenzyl bromide,
3-bromobenzyl chloride,
3-bromobenzyl bromide,
4-bromobenzyl bromide,
3-methylbenzyl chloride,
3-methylbenzyl bromide,
4-methylbenzyl chloride,
4-methylbenzyl bromide,
4-t-butylbenzyl bromide,
2-trifluoromethylbenzyl chloride,
2-trifluoromethylbenzyl bromide,
4-trifluoromethylbenzyl chloride,
4-trifluoromethylbenzyl bromide,
4-vinylbenzyl chloride,
chloro-diphenylmethane,
bromo-diphenylmethane,
triphenylmethyl chloride,
triphenylmethyl bromide,
chloro(4-chlorophenyl)-phenylmethane,
chlorobis(4-fluorophenyl)-methane.
The compound (23) as the synthesis material ketones of the compound (eH) is shown below more illustratively;
acetophenone,
propiophenone,
butyrophenone,
isobutyrophenone,
valerophenone,
2,2-dimethylpropiophenone,
4xe2x80x2-methylpropiophenone,
3xe2x80x2-methylacetophenone,
4xe2x80x2-methylacetophenone,
4xe2x80x2-ethylacetophenone,
4xe2x80x2-butylacetophenone,
2xe2x80x2-methoxyacetophenone,
3xe2x80x2-methoxyacetophenone,
3xe2x80x2-(trifluoromethoxy)-acetophenone,
4xe2x80x2-(trifluoromethoxy)-acetophenone,
4xe2x80x2-ethyoxyacetophenone,
2xe2x80x2-nitroacetophenone,
4xe2x80x2-nitroacetophenone,
benzophenone,
2-methylbenzophenone,
3-methylbenzophenone,
4-methylbenzophenone,
4-benzobiphenyl,
2,4-diphenylbenzophenone,
2,5-diphenylbenzophenone,
3,4-diphenylbenzophenone,
3-(trifluoromethyl)-benzophenone,
4-(trifluoromethyl)-benzophenone,
3,3xe2x80x2-bis (trifluoromethyl)-benzophenone,
3,4xe2x80x2-bis (trifluoromethyl)-benzophenone,
4-methoxybenzophenone,
3,3xe2x80x2-dinitrobenzophenone.
In the synthesis of the compound (1) of the invention, purification of a compound of interest from the reaction mixture is carried out by employing usually used techniques in the field of chemical synthesis, namely by effecting separation extraction of the reaction product between water and an organic solvent which does not optionally mixed with water, such as benzene, toluene, ethyl acetate, butyl acetate, methyl isobutyl ketone, chloroform, dichloromethane or the like, and then carrying out concentration, crystallization and the like. Also, as occasion demands, fractional purification may be carried out for example by a column chromatography using alumina, silica gel, adsorption resin or the like.
Being an amine, the compound (I) of the invention exists as a base. In consequence, it forms salts with a number of inorganic and organic acids, and such a property is applied to the production of pure substance and its provisional forms as pharmaceutical preparations. That is, in its production process, acidification of the compound renders possible its solubilization and extraction purification in water or the like polar solvent so that it can be isolated as a salt having desirable physicochemical properties, and, in applying it to pharmaceutical preparations, it can form a pharmacologically acceptable salt. Examples of the salt to be formed include acid addition salts with hydrochloric acid, nitric acid, hydrobromic acid, sulfuric acid, phosphoric acid and the like inorganic acids or with aliphatic monocarboxylic acids, dicarboxylic acids, hydroxyalkanoic acids, hydroxyalkanoic diacids, amino acids and the like, as well as salts derived from aromatic acids, aliphatic and aromatic sulfonic acids and the like nontoxic organic acids. Examples of such acid addition salts include hydrochloride, hydrobromide, nitrate, sulfate, hydrogensulfate, phosphate, monohydrogenphosphate, dihydrogenphosphate, acetate, propionate, tartarate, oxalate, malonate, succinate, fumarate, maleate, mandelate, benzoate, phthalate, methanesulfonate, benzenesulfonate, toluenesulfonate, citrate, lactate, malate, glycolate and the like.
These acid addition salts described above are significant also as pharmacologically acceptable pharmaceutical compositions, and it seems that they have advantages as pharmaceutical compositions in terms of the preparation of medicaments and of the dispersing and absorbing abilities when administered to the human body.
A pharmaceutical composition which contains the compound of the invention as an active ingredient can be administered to human and animals other than human, through the route of either oral administration or parenteral administration (e.g., intravenous injection, intramuscular injection, subcutaneous injection, rectal administration or percutaneous absorption). Thus, the pharmaceutical composition containing the compound of the invention as an active ingredient can be made into appropriate dosage forms depending on each route of administration.
Illustrative examples of dosage forms include tablets, capsules, powders, granules, syrups and the like as oral preparations and intravenous, intramuscular and the like injections, rectal administration preparations, oleaginous suppositories, aqueous suppositories and the like as parenteral preparations.
Each of these various preparations can be produced in the usual way making use of generally used fillers, disintegrators, binders, lubricating agents, coloring agents and the like.
Lactose, glucose, corn starch, sorbitol, crystalline cellulose and the like can be exemplified as the fillers, starch, sodium alginate, gelatin powder, calcium carbonate, calcium citrate, dextrin and the like can be cited as the disintegrators, dimethyl cellulose, polyvinyl alcohol, polyvinyl ether, methyl cellulose, ethyl cellulose, acacia, gelatin, hydroxypropyl cellulose, polyvinyl pyrrolidone and the like can be exemplified as the binders and talc, magnesium stearate, polyethylene glycol, hardened plant oil and the like can be exemplified as the lubricating agents. In addition, the aforementioned injections can be produced by further adding a buffer, a pH adjusting agent, a stabilizing agent and the like as occasion demands.
Though the amount of the compound of the invention in the pharmaceutical composition varies depending on its dosage forms, it may be used in an amount of generally from 0.1 to 50% by weight, preferably from 0.1 to 20% by weight, based on the total camposition. Its dose is optionally decided in each case, taking age, body weight, sex, difference in diseases, degree of symptoms and the like of each patient into consideration, but the dose is within the range of generally from 0.1 to 100 mg, preferably from 0.1 to 30 mg, per day per adult, and the daily dose is administered once a day or by dividing it into several doses per day.